This project began in 1978 with the aim of testing the relationship between a low level of response to alcohol and the alcoholism risk. During the subsequent ten years, 453 drinking but not alcohol dependent sons of alcoholic fathers and family history negative controls were evaluated through a series of increasingly complex research paradigms. These each measured the levels of changes in subjective feelings and physiological responses to clinically relevant intoxicating doses of alcohol. By 1988, the data had consistently demonstrated that a low level of response to alcohol (or the need for larger amounts of alcohol to have an effect) characterized about 40 percent of the sons of alcoholics, but was only seen in less than 10 percent of the controls. During the next five years, subjects were followed to determine whether the low level of response to alcohol at approximately age 20 predicted alcohol abuse or dependence. All 453 men were located, and personal interviews were carried out with the subject and an additional informant for 450. The data demonstrated that the low response to alcohol was a potent predictor of future alcoholism, explaining the majority of the ability of a family history of alcoholism to predict severe alcohol problems. The most recent five year protocol, which began in 1994, located all of the original subjects, interviewed subjects and their spouses, and tested how six additional areas of life functioning relate to a family history of alcoholism and the level of response to alcohol in predicting (or protecting from) severe alcohol problems. These additional domains included levels of boredom susceptibility, work stress, expectations of the effects of alcohol, and so on. During the five years beginning in 1999 subjects will be reevaluated, extensive data gathered regarding the personal and family histories of the spouse, and detailed information will be obtained regarding their projected 555 sons and daughters. The offspring will offer information regarding how the level of response to alcohol and additional important domains relate to the family histories of both the original subjects and their spouses in predicting the initiation of alcohol use, alcohol problems, substance-related problems, and mental health problems in the next generation.